The role of Clusterin in cerebral amyloid angiopathy

 描述(申请人提供)：阿尔茨海默病(AD)是痴呆症最常见的原因，其特征是由淀粉样蛋白(Aβ，Aβ)多肽沉积形成的细胞外斑块和由过度磷酸化形式的tau蛋白组成的细胞内缠结。AD的另一种常见病理是脑淀粉样血管病，由Aβ沉积在脑血管壁导致血管功能障碍和出血引起。载脂蛋白E基因的ε4等位基因是阿尔茨海默病和慢性再生障碍性贫血的最强的遗传危险因素，但最近的多项全基因组关联研究证明，类似的载脂蛋白聚集素(CLU)也是AD的危险因素。CLU在CAA中的作用尚不清楚，但我们有强有力的证据表明，CLU在CAA的形成中起着至关重要的作用。虽然人们对载脂蛋白E受体的生物学了解很多，但唯一已知的Clu受体LRP2/megalin在成人大脑中的表达非常低，这表明还有其他受体存在但尚未被发现。我们发现Plexin A4(PLXNA4)是一种新的受体，它调节小鼠和人类细胞外CLU的水平。与对照组相比，阿尔茨海默病小鼠模型和人类阿尔茨海默病脑组织中PLXNA4水平显著降低。这项建议的目的是明确CLU如何调节Aβ在脑实质和脑血管中的代谢和沉积。结合细胞培养、生物化学、小鼠遗传学、药理学和病理定义的人体组织，我们将通过研究功能终点，如组织病理学、血管功能障碍、神经性营养不良、电生理学和行为，确定CLU和PLXNA4如何影响AD。鉴于CLU在这些领域的新兴作用，破译这一途径不仅可能导致AD的新治疗靶点，而且还可能导致中风和乳腺癌的新治疗靶点。

 DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia and is characterized by extracellular plaques formed by the deposition of amyloid-β (Aβ) peptide and intracellular tangles comprised of hyperphosphorylated forms of the tau protein. Another common pathology in AD is cerebral amyloid angiopathy (CAA), caused by Aβ deposition in the walls of cerebral vessels leading to vascular dysfunction and hemorrhage. The strongest genetic risk factor for both AD and CAA is ε4 allele of the apolipoprotein E (APOE) gene, but multiple recent genome-wide association studies have proven that a similar apolipoprotein, Clusterin (CLU), also confers risk for AD. The role of CLU in CAA is unknown, but we have strong evidence that CLU is critically involved in the formation of CAA. While much is known about apoE receptor biology, the only known receptor for Clu, LRP2/Megalin, is very poorly expressed in the adult brain, suggesting other receptors are present but undiscovered. We have found that Plexin A4 (PLXNA4) is a novel receptor that regulates the levels of extracellular CLU in mice and in humans. PLXNA4 levels are significantly decreased in mouse models of AD as well as human AD brain tissue compared to controls. The objective of this proposal is to define how CLU regulates Aβ metabolism and deposition in brain parenchyma and cerebrovasculature. Using a combination of cell culture, biochemistry, mouse genetics, pharmacology, and pathologically defined human tissue, we will determine how the CLU and PLXNA4 affect AD by studying functional endpoints such as histopathology, vascular dysfunction, neuritic dystrophy, electrophysiology, and behavior. Deciphering this pathway could lead to new therapeutic targets not only for AD, but also for stroke and breast cancer, given the emerging role of CLU in those respective fields.